This application is the national phase under 35 U.S.C. xc2xa7371 of PCT International Application No. PCT/IB99/01569 which has an International filing date of Sep. 22, 1999, which designated the U.S.A.
This invention relates to oxihumic acid and its use in the treatment of various conditions.
Humic acids are formed during the decomposition of organic matter and can therefore be found in practically all natural environments in which organic materials and micro-organisms are, or have been present (Visser, 1973). Humic acids have been used in medicines at a dosage of between 0.9 and 1.8 g daily for the treatment of hyperacidity and other gastric disturbances in humans (Gramsch, 1961; Reichert, 1966). No unfavourable side effects have been observed at the above-mentioned doses.
Humic acids have also been successfully used as anti-inflammatory agents because of their local anti-inflammatory, hyperaemic and analgesic properties (Salz, 1974; Motohisa et al., 1974) and as a systemic treatment for anaemia and hypercholesterolaemia (Soloveyva and Lotosh. 1984).
Peat extracts have been used in therapeutic baths for the treatment of various conditions for many years (Brandt, 1964; Eichelsdxc3x6rfer, 1976). The antiseptic properties of peat were first recognised during World War 1 when it was applied directly on to battle wounds to prevent infection (Haanel, 1924). The possible application of coal-derived humic acid and fulvic acid as antimicrobials, has recently been investigated by Cloete et al. (1990) of the Department of Microbiology, University of Pretoria.
More recently, humate has been used in the treatment of Von Willebrand disease (Lopez-Fernandez et al., 1992). Patients were treated with an infusion of 35 mg/kg body weight after which normal VIII levels were achieved.
It has been reported that humic acids derived from either the decomposition of organic matter (Sato et al., 1986) or the oxidation of coal (Bernacchi et al., 1996) do not act as mutagens, but interestingly, may rather on the other hand behave as desmutagens (Takahiko et al., 1986) by inhibiting the mutagenicities of selected mutagens.
The anti-tumour properties of humic acids were first investigated in vivo by Zsindely et al. (1971) who reported that mice which received 10-40 mg humic acids orally for 5 days after experimental induction of cancer by administration of ascites sarcoma or lymphoma (IP) showed a greatly reduced tumour load 10 days later. They also found that the humic acid treatment resulted in a 20-25% decrease in the RNA and DNA content of tumour cells. Humic acids have also been shown to control uterine cancer in rats (Davies, 1996).
Since they are highly surface-active (Visser, 1982), these acids may act on the membranes of malignant cells, which often differ in structure and function of normal cells (Bennet and Connon, 1957). Adamek (1976) reported that a peat preparation administered orally, rectally or intramuscularly at tumour sites resulted in their arrest or regression.
Antiviral properties, at a concentration of 100 xcexcg/ml of ammonium humate in vitro have been described by Thiel et al. (1981) resulting in the successful use of this agent as a topical treatment for herpes virus-induced skin diseases (Klxc3x6cking et al., 1983). Schneider et al. (1996) reported on the anti-HIV activity of synthetic humate analogues derived from hydroquinone. These compounds inhibited HIV-1 infection of MT-2 cells with an impressively low IC50 of 50-300 ng/ml. The infectivity of HIV particles was inhibited by interference with the CD4-induced proteolytic cleavage of the V3-loop of virion gp120SU.
According to a first aspect of the invention, there is provided a humic acid, salt, ester or derivative thereof, for use in the manufacture of a medicament for use in stimulating lymphocytes in a subject.
According to a preferred form of the invention, there is provided the use of a humic acid, salt, ester or derivative thereof, in the manufacture of a medicament for use in stimulating the TH1 and TH2 lymphocytes in a subject. Stimulation of the TH1 and TH2 lymphocytes in a subject allows the medicament to be used, for example, in the treatment of viral and bacterial infections, and more particularly HIV infections, cancer and opportunistic diseases.
The invention provides, according to a particularly preferred aspect, a medicament of the type described above for oral administration. It has been found that the humic acid, salt, ester or derivative thereof is rapidly taken up by the subject if administered orally.
The invention further provides a method of stimulating lymphocytes in a subject which includes the steps of administering a humic acid, salt, ester or derivative thereof, to the subject. The amount of humic acid, salt, ester or derivative thereof, administered to the subject will be effective to stimulate lymphocytes in the subject.
The subject may be a human, animal or bird.
Examples of specific uses of the humic acid, salt, ester or derivative thereof are inhibiting, viral and bacterial infections, inhibiting cancer growth, the treatment of myalgic encephalitis (ME) associated with viral infections and a depressed immune system, inflammation, pain and fever.
The active ingredient in the practice of the invention is humic acid, a salt, ester or derivative thereof. Humic acid is a complex mixture of macromolecular organic substances which are not soluble in water under acidic conditions, i.e. at pH below 2, but are soluble at higher pH values.
The invention has particular application to a humic acid which may be produced, for example, by the wet oxidation process described in U.S Pat. No. 4,912,256. Such humic acid is hereinafter referred to as xe2x80x9coxihumic acidxe2x80x9d. The potassium or sodium salt of a humic acid, particularly oxihumic acid, may be produced by the method described in U.S. Pat. No. 5,004,831. Oxihumic acid also has no defined structure. It is a complex mixture of organic compounds. It is acidic in nature, due to its carboxylic and phenolic groups. Oxihumic acid is practically insoluble at low pH in water, but becomes soluble in alkaline aqueous medium.
Oxihumic acid can, therefore, be regarded as a relatively high molecular mass product containing carboxylic and phenolic groups. Oxihumic acid compared to so-called natural humic acids has a relatively high degree of aromaticity. A typical functional group analysis of oxihumic acid is given below:
The humic acid, salt, ester or derivative thereof will preferably be provided in a pharmaceutical composition form suitable for oral administration. A particularly suitable form is a capsule. The active ingredient may be present in the capsule with or without excipients.
The invention provides according to yet another aspect, a pharmaceutical composition comprising oxihumic acid, salt, ester or derivative thereof, as an active ingredient. The composition has particular application in the treatment and the control of viral infections such as HIV infections, and cancer. For these applications, the composition is preferably administered orally.